The overall goal of this Program Project is to investigate how serotonergic neurotransmission modulates many important behaviors. Abnormalities in 5-hydroxytryptamine (5-HT, serotonin) neurotransmission have been implicated in the pathogenesis of diverse psychiatric disorders, and various classes of psychotherapeutic agents have prominent effects of different aspects of synaptic transmission mediated by 5-HT. Studies in this Program Project specially focus on the function of 5-HT1A receptors because of their role in mediating the effects of serotonergic antidepressant and anti-anxiety drugs. This Program Project employs a multi-disciplinary approach to study a number of outstanding critical questions concerning the role of 5-HT1A receptors in modulating serotonergic neurotransmission at the behavioral systems, cellular and molecular levels of analysis. A common theme developed by all of the projects in the Program is that molecular genetics now provides the technology to alter the function of genes that are associated with specific neurotransmitter receptors in mammals. Recently developed tissue-specific and inducible knockout preparations provide the ability to address novel questions concerning the developmental neurobiology and neural circuitry of 5-HT linked to behavior in novel and creative ways. Another common theme appearing in all of the projects is the need to elaborate the role of individual 5-HT circuits that contribute to the developmental expression of emotional behaviors or to the action of psychotherapeutic drugs, such as the SSRIs. The functional significance of this circuitry will be established by systematically comparing the properties of 5-HT receptors in different 5-HT circuits using behavioral, in vivo microdialysis, electrophysiological, neuroimaging and molecular genetics techniques. The development of neuroimaging methods for visualizing 5-HT1A and 5-HT tranporters in mouse will provide the ability to characterize genetic alterations of these receptors or to follow the regulation of these receptors during chronic drug treatments in the brains of living animals. Taken together, the integrative studies of this Program Project will provide new information on the biology of serotonin in behavior and psychopathology with an emphasis on genetic regulation, neural circuitry and the pharmacology of antidepressant drugs. The results of the proposed work should have important implications for our understanding of synaptic transmission in the brain and of the effect of psychotherapeutic drugs.